Acute effects of intravenous cyclosporine on blood pressure, renal hemodynamics, and urine prostaglandin production of healthy humans.
The acute renal failure associated with cyclosporine may result from vasoconstriction of intrarenal arterioles. To evaluate the mechanism of cyclosporine-induced nephrotoxicity, we acutely administered cyclosporine to eight healthy female volunteers with normal blood pressure and renal function. Cyclosporine (4 mg/kg) in 250 ml of 5% dextrose in water (D5W) was administered as a steady intravenous infusion over 6 hr. Glomerular filtration rate and renal plasma flow were measured by serum disappearance of 99m TcDTPA and 131I hippuran, respectively, during the last 3 hr of the infusion. D5W was given to the patients on separate days before the cyclosporine infusion to obtain control data. Systolic and diastolic blood pressure measured every hour during the infusions and renal vascular resistance were slightly higher during cyclosporine administration, but the increases were not statistically significant. Renal plasma flow was not affected by cyclosporine, being 479.6 +/- 24.9 ml/min during the control infusion and 463.3 +/- 12.7 ml/min during the cyclosporine infusion. However, glomerular filtration rate was reduced by cyclosporine in all patients (control, 108.8 +/- 2.5 ml/min, vs. cyclosporine, 91.1 +/- 2.2 ml/min, P less than .01), except one who demonstrated no significant change. Urinary excretion of thromboxane B2 during cyclosporine administration was markedly increased in all patients, being 39.9 +/- 8.2 ng/hr in the control period and 85.8 +/- 22.3 ng/hr during cyclosporine infusion (P less than .05), except for the one patient in whom no decrease in GFR was noted. There was no significant change in the urinary excretion rate for 6-keto-prostaglandin F1a or prostaglandin E during cyclosporine infusion. Serum averaged levels of peripheral renin activity, angiotensin II, and aldosterone did not change during with the cyclosporine administration compared with the control. All patients demonstrated a decrease in 24-h urinary excretion of sodium and potassium on the day of the cyclosporine infusion. Verapamil SR (240 mg daily for 7 days prior to cyclosporine infusion) did not reverse the reduction in glomerular filtration rate induced by cyclosporine; however, a significant reduction in renal vascular resistance and an increase in renal plasma flow (P less than .05) were noted when the volunteers were treated with both verapamil and cyclosporine compared with cyclosporine alone. Intravenous infusion of Cremophor EL, the vehicle to dissolve cyclosporine, demonstrated no significant effects on blood pressure, renal hemodynamics or urinary prostaglandin excretion.(ABSTRACT TRUNCATED AT 400 WORDS)
Weir
M R
MR
Department of Medicine, University of Maryland Hospital, Baltimore 21201.
Klassen
D K
DK
Shen
S Y
SY
Sullivan
D
D
Buddemeyer
E U
EU
Handwerger
B S
BS
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects*; D003524:Cyclosporins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004573:Electrolytes / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D011453:Prostaglandins / Q000652:urine*; D012079:Renal Circulation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000096:biosynthesis; D014700:Verapamil / Q000494:pharmacology
D003524:Cyclosporins; D004573:Electrolytes; D011453:Prostaglandins; D013929:Thromboxane B2; D014700:Verapamil